Selective leptin resistance revisited
Open accessAbstract
In addition to effects on appetite and metabolism, leptin influences many neuroendocrine and physiological systems, including the sympathetic nervous system. Building on my Carl Ludwig Lecture of the American Physiological Society, I review the sympathetic and cardiovascular actions of leptin. The review focuses on a critical analysis of the concept of selective leptin resistance (SLR) and the role of leptin in the pathogenesis of obesity-induced hypertension in both experimental animals and humans. We introduced the concept of SLR in 2002 to explain how leptin might increase blood pressure (BP) in obese states, such as diet-induced obesity (DIO), that are accompanied by partial leptin resistance. This concept, analogous to selective insulin resistance in the metabolic syndrome, holds that in several genetic and acquired models of obesity, there is preservation of the renal sympathetic and pressor actions of leptin despite attenuation of the appetite and weight-reducing actions. Two potential overlapping mechanisms of SLR are reviewed: 1) differential leptin molecular signaling pathways that mediate selective as opposed to universal leptin action and 2) brain site-specific leptin action and resistance. Although the phenomenon of SLR in DIO has so far focused on preservation of sympathetic and BP actions of leptin, consideration should be given to the possibility that this concept may extend to preservation of other actions of leptin. Finally, I review perplexing data on the effects of leptin on sympathetic activity and BP in humans and its role in human obesity-induced hypertension.
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Leptin infusions in rodents over several days cause mild, gradual increases in blood pressure and heart rate.
“Leptin infusions in rodents over several days also cause mild, gradual increases in BP and HR125–127.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [126]
Although the suppressive effects of leptin on food intake are blunted in obesity, its acute stimulatory actions on renal sympathetic nerve activity seem to be preserved, suggesting selective leptin resistance.
“Although the suppressive effects of leptin on food intake are blunted in obesity, its acute stimulatory actions on RSNA seem to be preserved, suggesting selective leptin resistance126,136.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [126]
Leptin receptors are expressed in many areas of the brain, including the ventromedial hypothalamus, arcuate nucleus, dorsomedial hypothalamus, brainstem vasomotor centers, and spinal cord intermediolateral nucleus.
“Leptin receptors (LepR) are expressed in many areas of the brain, including the ventromedial hypothalamus, arcuate nucleus (ARC) and dorsomedial areas of the hypothalamus, as well as in vasomotor centers of the brainstem and spinal cord intermediolateral nucleus (IML)93.”
From Obesity-Induced Hypertension: Interaction of Neurohumoral and Renal Mechanisms (2015) · cites this paper as [93]
Leptin is less effective in suppressing appetite in obese compared to lean experimental animals.
“Leptin is less effective in suppressing appetite in obese compared to lean experimental animals93.”
From Obesity-Induced Hypertension: Interaction of Neurohumoral and Renal Mechanisms (2015) · cites this paper as [93]
Leptin contributes to sympathetic overactivity and hypertension in a number of animal models of monogenic and diet-induced obesity.
“A large body of evidence has demonstrated that leptin contributes to sympathetic overactivity and hypertension in a number of animal models of monogenic and diet-induced obesity74–77.”
From The Sympathetic Nervous System Alterations in Human Hypertension (2015) · cites this paper as [77]
Data from several studies in relatively large numbers of lean and obese subjects have failed to show an increase in blood pressure with chronic or acute administration of leptin.
“There are, however, data from several studies in relatively large numbers of lean and obese subjects that have failed to show an increase in blood pressure with chronic or acute administration of leptin77.”
From The Sympathetic Nervous System Alterations in Human Hypertension (2015) · cites this paper as [77]
Evidence that leptin contributes to obesity-associated hypertension in humans is inconclusive.
“Surprisingly then, evidence that leptin contributes to obesity-associated hypertension in humans is inconclusive77.”
From The Sympathetic Nervous System Alterations in Human Hypertension (2015) · cites this paper as [77]
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- Authors
- Mark, A. L.
- Affiliations
- University of Iowa (US)
- Corresponding author
- Mark, Allyn L.
- ORCID
- Mark, Allyn L.
- Venue
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
- Publisher
- American Physiological Society
- Published
- 2013-09-15
- Volume
- 305
- Issue
- 6
- Pages
- R566-R581
- ISSN
- 0363-6119 (ISSN-L)
- 1522-1490
- PMC
- PMC3763044
- OpenAlex
- W2064109637
- Cited by
- 162
- References
- 165
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 12 · 2023: 6 · 2022: 6 · 2021: 16 · 2020: 13 · 2019: 12 · 2018: 11 · 2017: 14 · 2016: 17 · 2015: 19 · 2014: 22 · 2013: 3
- FWCI
- 2.45
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p50hl044546-05)
- National Heart, Lung, and Blood Institute (HL-55006, HL-96571, R01HL063887, HL-63887, HL-14388, HL-84207, HL-44546, P50HL055006, P01HL014388, P01HL084207, P01HL096571)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- leptin, obesity-related hypertension, diet-induced obesity, sympathetic nervous system, blood pressure regulation, leptin signaling, appetite regulation
- MeSH terms
- Animals, Brain, Humans, Hypertension, Myocardium, Obesity, Sympathetic Nervous System, Leptin
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